This invention relates to controlling the cellular immune/inflammatory responses, particularly phagocyte-mediated tissue injury and inflammation.
Circulating phagocytic white blood cells are an important component of the cellular acute inflammatory response. It is believed that a number of important biological functions such as chemotaxis, immune adherence (homotypic cell adhesion or aggregation), adhesion to endothelium, phagocytosis, antibody-dependent cellular cytotoxicity, and histaminase and lysosomal enzyme release are mediated by a leukocyte surface glycoprotein receptor, known as complement receptor type 3 (CR3), also known as Mol, CD11b/CD18, Mac-1 or MAM. See, Arnaout et al., J. Clin. Invest. 72:171-179 (1983), and references cited therein; Dana et al., J. Immunol. 137:3259-3263 (1986); Wallis et al., J. Immunol. 135:2323-2330 (1985); Arnaout et al., New Eng. J. Med. 312:457-462 (1985); Dana et al., J. Clin. Invest. 73:153-159 (1984); and Beatty et al., J. Immunol. 131:2913-2919 (1983).
CR3 consists of two noncovalently associated subunits. Kishimoto et al., Cell 48:681-690 (1987); Law et al., Eur. Mol. Biol. Organ. J. 6:915-919 (1987). The alpha subunit has an apparent molecular mass of 155-165 kD and associates in a divalent cation-independent manner with a beta subunit of 95 kD. Todd et al., Hybridoma 1:329-337 (1982). The beta subunit is common to two other leukocyte surface glycoproteins, LFA-1 and p150,95. In addition to sharing the property of binding to the same beta subunit, CR3, LFA-1, and p150,95 leukocyte adhesion molecules require divalent cations to mediate their adhesion functions, and they have homologous NH.sub.2 -termini. Pierce et al., Biochem. Biophys. Acta. 874:368-371 (1986); Miller et al., J. Immunol. 138:2381-2383 (1987).
Monoclonal antibodies have been used to identify at least two distinct functional domains of CR3, one mediating adhesion and the other mediating binding to the complement C3 fragment (iC3b). See, Dana et al., J. Immunol. 137:3259-3263 (1986).
Cosgrove et al., Proc. Nat'l. Acad. Sci. USA 83:752-756 (1986) report a human genomic clone which produces "a molecule(s)" reactive with monoclonal antibodies to CR3.alpha. (Mac-1 or OKM1).
Sastre et al., Proc. Nat'l. Acad. Sci. USA 83:5644-5648 (1986) report a mouse genomic clone coding for the .alpha. subunit of mouse complement receptor type 3.
It is believed that CR3 and p150,95 mediate enhanced adhesiveness of activated phagocytes through increased expression of these proteins on the surface of activated cells. For example, in granulocytes, these proteins are translocated from intracellular storage pools present in secondary and tertiary granules. Arnaout et al., J. Clin. Invest. 74:1291-1300 (1984); Arnaout et al., New Eng. J. Med. 312:457-462 (1985); Todd et al., J. Clin. Invest. 74:1280-1291 (1984).
Inherited deficiency of CR3 impairs leukocyte adhesion-dependent inflammmatory functions and predisposes to life-threatening bacterial infections. Dana et al., (1984), cited above.
Simpson et al., J. Clin. Invest. 81:624 (1988) disclose that a monoclonal antibody directed to an adhesion-promoting domain of CR3.alpha. reduces the extent of cardiac damage in dogs associated with myocardial infarction, presumably by limiting reperfusion injury.